Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a 90 kDa auto-antigen reported to be expressed in hepatocellular carcinoma of cancer patients (Hoo et al. 2002). CIP2A is believed to be an oncoprotein, and has a diverse array of functions including the inhibition of protein phosphatase 2A (PP2A) via dephosphorylation of c-Myc. CIP2A is hypothesized to stabilize c-Myc activity, probably via the dephosphorylation of c-Myc at its amino acid 62 position of serine (S62) (Junttila and Westermarck, 2008). Li et al. and Côme et al. similarly disclose CIP2A's interaction with c-Myc. CIP2A may play a role in progression of cancers, including human cervical, gastric, and breast cancers (Junttila et al. 2007; Li et al. 2008; Côme et al. 2009).
Increased expression of CIP2A is reported in tissue samples from gastric, breast, oral, prostate, cervical, esophageal squamous cell, and non-small cell lung cancer, colon, ovarian and colorectal patients (Khanna et al. 2009; Katz et al. 2010; Vaarala et al. 2010; Liu et al. 2011; Qu et al. 2010; Dong et al. 2011). The increased expression of CIP2A in breast, non-small cell lung and early stage tongue cancer is found to be correlated with poor prognosis and therefore may serve as a biomarker for cancer disease progression (Khanna et al. 2008; Dong et al., 2011; Böckelman et al. 2011).
Considering the increased expression of CIP2A in various types of cancer and its putative role in cancer progression through inhibition of PP2A tumor suppressor activity, it is important to identify and characterize transcription factors that regulate CIP2A gene promoter and thus CIP2A gene regulation. However, scare information exists regarding CIP2A promoter regulation. Recently, Khanna et al. (2011) disclosed a role of a transcriptional factor (Ets1) in transcriptional regulation of CIP2A in human gastric and prostate cancer cells. These authors further speculated that Ets1 may act via the mitogen activated protein kinase signaling cascade. The exact role of Ets1 and other potential transcriptional factors requires confirmation. The transcriptional elements regulating the expression of CIP2A still remain unclear. Furthermore, whether the proposed transcriptional regulation may be applicable in other cancer cells is unknown.
There is a continuing need in understanding the transcriptional regulation of CIP2A and in identifying means to suppress the expression of CIP2A and attenuate cancer development. The present invention provides a novel approach to use siRNA to influence the CIP2A promoter activity and thus altering the cancer pathogenesis in human.